Flavonoid Fields Forever

The fields are ripe with a variety of flavonoids offering health benefitsderived from strawberries, blackberries, pomegranate, citrus, broccoli and cauliflower to mention a few. Indeed this field s not lacking in research nor have scientists stopped investigating new origins, mechanisms of act on and potent al anti-cancer effects for these biological compounds. In the past 20 years, flavonoids have gained interest because of the beneficial health effects for their anti-inflammatory, cardio-protective and anti cancer activities.

It is for these reasons there has been a dramatic increase in the consumption and use of dietary supplements containing high concentrations of plant flavonoids.¹ According to Business Insights, the market potential for flavonoids in the dietetic and nutritional supplement market is in excess of $862 million for 2007, with annual increases of 12 percent forecasted.

The International Union of Pure and Applied Chemistry (IUPAC) classifies the more than 6,000 different compounds that make up the category of flavonoids into three groups: flavonoids, isoflavonoids and neoflavonoids. Many flavonoids in plants are molecularly bound to sugar, forming glycosides (as opposed to those not bound to sugar, aglycones). The flavonoid subgroups consist mainly of anthocyanins, flavanols, flavanones, flavones and isoflavones. All are naturally-occurring phytochemicals abundantly present in fruits, vegetables, and beverages such as wine and tea.

In general, dietary intakes of flavanones, anthocyanidins and certain foods rich in flavonoids are associated with reduced risk of death due to coronary heart disease (CHD), cardiovascular disease (CVD), although a recent study in post-menopausal women found no association between flavonoid intake and stroke mortality.² More specifically, individual flavonoid-rich foods associated with significant mortality reduction include the flavonoids in bran (added to foods; associated with preventing stroke and CVD); apples, pears and red wine (associated with preventing CHD and CVD); grapefruit for its link to CHD; and strawberries for cardiovascular health. Cocoa is also connected to reduced risk of CVD.

Flavonoids are ripe with health benefits as their pharmacological effect is mainly due to their antioxidant activity and inhibition of certain enzymes. However, despite copious data, the mechanisms behind these effects are not fully understood.

Flavonoids as antioxidants have been challenged recently by research done on their bioavailability, which indicate they reach only very low concentrations in human plasma after the consumption of flavonoid-rich foods.3 In addition, most flavonoids are extensively metabolized in vivo, which can affect their antioxidant capacity. Furthermore, fruits and vegetables contain many macro- and micronutrients, in addition to flavonoids, that may directly or through their metabolism affect the total antioxidant capacity of plasma. Balz Frei, Ph.D., professor and director of the Linus Pauling Institute at Oregon State University, Corvallis, noted there have been controversial developments on the antioxidant capacity of flavonoids.

What we now know is that flavonoids are highly metabolized, which alters their chemical structure and diminishes their ability to function as an antioxidant, Frei said, though he added he also validates their clinical potency. If you measure the activity of flavonoids in a test tube, they are indeed strong antioxidants. Based on laboratory tests of their ability to scavenge free radicals, it appears they have three to five times more antioxidant capacity than vitamins C or E.

Freis research, supported by the American Heart Association (AHA) and the National Center for Complementary and Alternative Medicine (NCCAM), found flavonoids appear to strongly influence cell signaling pathways and gene expression, with relevance to both cancer and heart disease. This process of gearing up to get rid of unwanted compounds is inducing so-called Phase II enzymes that also help eliminate mutagens and carcinogens, and therefore may be of value in cancer prevention, he said.

Berry Good Stuff

Many popular foods are rich dietary sources of flavonoids. Anthocyanins (ACNs) are the pigments seen in richly-colored red, blue and purple fruits and vegetables such as raspberries, strawberries, blackberries, blueberries, bilberries, plums, eggplant, red cabbage, red onion and grapes (red and purple). It is those anthocyanins from the grape that deliver the flavonoid content in red wine.

Common anthocyanins include cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin; the types of anthocyanins vary depending on the foods, as do the concentrations. For example, concentrations of total ACNs varied considerably from 0.7 to 1,480 mg per 100 g of fresh weight in gooseberry and chokeberry fruit, respectively.⁴ According to updated food intake data from the U.S. National Health and Nutrition Examination Survey (NHANES 2001- 2002), daily intake of ACNs is estimated to be 12.5 mg/d per person. Of the different anthocyanins, aglycones, cyanidin, delphinidin, and malvidin were estimated to contribute 45, 21 and 15 percent, respectively, of total ACN intake.

The benefits from flavonoids in the human eye are similar to those also transferred to plants, including absorption of ultraviolet (UV) radiation, protection from pathogens, activation of growth and differentiation factors, and antioxidant protection. Popular flavonoids studied for their antioxidant protection (pertaining to eye health) are berry anthocyanidins, tea catechins, and various herbal phytochemicals. It is specifically the anthocyanins in bilberries that have shown eye-protective abilities against the development of eye blindness and fatigue.^5,6,7

Those in cranberries have been found to combat cancer, kidney stones, gum disease and urinary tract infection.^8,9,10,11 Blueberries have also demonstrated protection against age-related neurodegenerative processes in the brain.^12,13 Similar protection is provided by strawberry flavonoids,¹⁴ which also protect the overall central nervous system in addition to chemoprotection of the liver and esophagus from cancer development.¹⁵ Another esophageal hero is the blackberry, which can inhibit tumor formation in the oral cavity,¹⁶ while also helping to curb colon cancer development.¹⁷

This fast-rising star, fresh off the vinethe black raspberryis one of natures most powerful antioxidant fruits. Particularly in the prevention of cancer, black raspberries are revealing remarkable effects as anti-tumor agents in laboratory research, said Paul Gross, Ph.D. (http://berrydoctor.com). Human clinical trials currently underway, and led by Gary Stoner, Ph.D., of Ohio State University, support daily consumption of lyophilized black raspberries to promote reductions in the urinary excretion of two markers of oxidative stress among patients with Barretts esophagus (a premalignant esophageal condition).¹⁸ Were currently looking at berry extracts and testing the ability of these extracts to inhibit the development and progression of cancer, said Stoner.

Blackberry is rather unique in that it contains one anthocyanidin, (cyaniding-3-0-glucoside (kuromanin). Results showed anthocyanidins in their methylated forms are very well distributed in the stomach, kidney, intestine and brain, said Greg Edmunds, vice president of marketing, Charles Bowman & Co. Probably the most important study in this area is one [rat study] where they show anthocyanidins present in brain tissue after ingestion. This was one of the first studies to show presence of metabolized anthocyanidin in the brain, possibly opening an exciting new formulation possibility for anthocyanidins as a brain antioxidant.

Preliminary ex vivo results have suggested proprietary pomegranate, blueberry, green tea, cranberry, aronia and black currant extracts can inhibit ACE activity, said John M. Hunter, vice president of business development at VDF Futureceuticals. Also, our combination of pomegranate, grape seed, green tea, aronia and black currant extracts (VitaBerry Plus®) exhibited ex vivo potency to modulate cholesteryl ester transfer protein (CETP) in human serum. Further testing will be done in humans under clinical conditions.

Beverage Benefits

Off another vine comes the grape. Researchers concluded grape seed extract (GSE) (as Activin®, from San Joaquin Valley Concentrates) may be significant in the treatment of skin rashes and other skin problems such as dermatitis, psoriasis, acne and arthritis, as well as cardiovascular disease and other inflammatory health concerns by inhibition of cell adhesion molecules in inflammation.¹⁹ In other research, Activin GSE reduced systolic blood pressure (BP) in normal and hypertensive rats.²⁰

Additionally, several proprietary studies funded by Polyphenolics Inc. (a division of Constellation Wines) showed anthocyanin- and proanthocyanidins-rich GSE (as MegaNatural® Gold) reduced arterial cholesterol accumulation caused by a high-fat diet and inhibited coconut oil saturated fatty acids from causing aortic endothelial dysfunction. Adjunct to healthy lifestyle modification, it may also effectively lower blood pressure in patients with metabolic syndrome.

And, for those not partaking in vino with dinner, grape extract comprising grape skins and seeds (asBioVin®, from Cyvex Nutrition) was found to deliver as much proanthocyanin, anthocyanin and trans-resveratrol content as one glass of red wine.²¹ Cheers to good health!

Resveratrol, one of the more famous phytochemicals, is found in red wine, specifically the skin and seeds of red and purple grapes and dark berries. Resveratrols most recent and intriguing health effect shown in laboratory studies is its broad-spectrum anticancer activity.

The online database of medical literature for the U.S. National Institutes of Health (NIH) cites nearly 500 publications over the past decade of research on resveratrol as a cancer chemopreventive nutrient, Gross said. Resveratrols actions to inhibit inflammatory mechanisms and the growth of new blood vessels in tumors, along with its ability to accelerate the rate of cancer cell death, are synergistic in anticancer activity.

Another beveragegreen teaboasts some of the most studied antioxidant flavonoids in the catechins. The treasures in teaepigallocatechin gallate (EGCG) and its little brother, EGCare both found in green and black tea. Both have been shown to reduce the risk of certain cancers, including prostate cancer,^22,23 due to their free radical scavenging before the onset of cancer-causing damage.²⁴

Fabulous Flavones

Flavone-rich foods include parsley, thyme, celery and hot peppers, while flavanones (hesperetin, naringenis, eriodictyol and tangeretin) are found in lemons, oranges, grapefruits and tangerines. Flavonoids, particularly flavones and flavonols, may account, at least in part, for the favorable role of plant foods on renal cell carcinoma (RCC). In an Italian case-controlled study conducted between 1994 and 2002, researchers found a correlation between major flavonoid classes and RCC.²⁵ In another such study, researchers suggest flavanone intake is inversely associated with esophageal cancer risk and may account, with vitamin C, for the protective effect of fruit, especially citrus fruit, on esophageal cancer.²⁶

A study out of the University of North Carolina, Chapel Hill found intake of flavonols, flavones, flavan-3-ols and lignans is associated with reduced risk of incident postmenopausal breast cancer among Long Island women. These results suggest U.S. women can consume sufficient levels of flavonoids to benefit from their potential chemopreventive effects.²⁷

Isoflavones could be considered the cousin of the main class of flavanoids; the specific types, daidzein and genistein, can be traced to both soy and red clover. Much research has been done documenting isoflavones benefits to cholesterol and endothelial function in heart disease;^{28,29, 30} risk of hormone-related cancers such as prostate cancer; ^{31, 32, 33} osteoporosis ^{34, 35} various parameters of gut health;^36,37 and attenuation of several pre-and post-menopausal symptoms.^38,39,40 In the most comprehensive study to date on prostate cancer, which included more than 43,000 men, researchers found the effects of isoflavones on prostate cancer development may differ according to disease stage. The present findings provide no clear understanding of when or how localized cancer will develop to aggressive cancer, and of the related effect of isoflavones, said the studys first author, Norie Kurahashi, M.D., of the Epidemiology and Prevention Division of the National Cancer Center, Japan.⁴¹ This could be due to isoflavones delaying the progression of latent prostate cancer only, as tumors lose estrogen-receptor beta expression and become aggressive.

Flavonol sources reach far and wide in agricultureincluding yellow onions, kale, scallions, leeks, broccoli, berries, apples, tea and various botanicals. Also rich in flavanols is cocoafound to acutely reverse endothelial dysfunction,⁴² inhibit diarrhea,⁴³ and promote vascular health.^{44,45,46,47,48} One study, conducted by Norman Hollenberg, M.D., Ph.D., from Harvard Medical School and Brigham and Womens Hospital, Boston, observed the effects of cocoa drinking on the Kuna people in Panama, and felt so strongly about this flavanol, he suggested epicatechin should be classed as a vitamin, being as important as penicillin and anaesthesia in terms of its potential impact on public health.⁴⁹

Quercetin, found in plants such as apples, onions and broccoli, is one of the most researched antioxidant flavanols. It flexed its muscle against oxidative stress and tissue damage associated with diabetes,⁵⁰ also showing promise in helping prevent bone loss.⁵¹Vitamin E in conjunction with flavonoid supplementation, including quercetin, inhibited COX-2 activity, posttranscriptionally.⁵² And lyophilized grape powder (LGP), which contained quercetin, as well as myricetin, kaempferol, flavans, anthocyanins and resveratrol, favorably altered lipoprotein metabolism (LDL, troglycerides andapoB/E), oxidative stress and inflammatory markers in both pre- and post-menopausal women.⁵³

And according to research presented at the Southeastern Regional Meeting of the American College of Sports Medicine in Charlotte, N.C. (2007), quercetin may help reduce illness and maintain mental performance in physicallys tressed test subjects (Appalachian State University). 

A Basket Full of Flavonoids

As the dominant benefits of flavonoids are related to their antioxidant activity, utilizing new advanced methods, researchers continue to look deeper into the mechanism behind flavonoids antioxidant function in supporting cardiovascular health, vision, anti-inflammatory activity, detoxification, liver support and morethrough natures basket of fruits and vegetables. There is very strong interest towards cruciferous/ brassica products (broccoli mainly), in liver support and detoxificationwhich is related to cancer prevention, said Tatiana Anguelova, Ph.D., director of technical services for Cyvex Nutrition, noting success of its cruciferous-derived products: BroccoPhane, BroccoSinolate and BroccoPlus.

Sharing the lead with cruciferous plants is the power of pomegranate. Pomegranates potent antioxidants along with its specific actions on several biochemical pathwayshas made pomegranate the focus of a wide range of research, including studies on vascular, cellular and heart health. Research indicates that in the case of pomegranate, nature may know best, since it is the natural ratio of polyphenolsalong with the natural levels of punicalaginsthat have displayed the greatest benefits in human studies, explains Blake Ebersole, marketing coordinator for Verdure Sciences.

One example of these benefits was found in a recently published clinical study published in the Journal of Agricultural and Food Chemistry (Nov. 2006), which demonstrated the natural spectrum pomegranate extract standardized to punical agins ( a s POMELLA® Extract, Verdure Sciences) can absorb and extensively metabolize in the body after consumption.⁵⁴ In addition, the study found a substantial (32 percent) increase in plasma antioxidant capacity (measured by plasma ORAC) at 30 minutes, which continued through eight hours after baseline.

Flavanoids Newer Facets

Applications for flavonoids are growing, as are new delivery methods. Skin is inaccording to Anguelova, there is a growing U.S. interest towards flavonoids for skin protection and rejuvenation. The health from within concept starts with the right flavonoidswhich, she explains, is not for topical use in cream preparations as you may thinkbut for oral intake. This trend has been growing for a long time in Japan and China and Europe and will pick up in the United States, she said. She cited an exampleApplezin (Cyvex Nutrition). As apple flavonoids have been proven to help prevent skin from ultraviolet (UV) damage, and also in skin lightening by suppressing melanin biosythesis. A newer flavonoid and free-B-ringflavanoids, derived from Scutellaria and Acacia plants, is Lasoperin from Unigen Pharmaceuticals. It exhibited an ability to suppress inflammation in the braina cause of cognitive dysfunction associated with aging.⁵⁵

We are seeing strong, enduring interest in all berry fruits [products], said Hunter, also pointing out the growing use for sprout-derived flavonoids. Additionally, we have observed novel uses and applications for many specific freeze dried sprout preparations as well as rationally designed blends (as SproutGarden®), he said.

Flavonoids are also enjoying attention for some of their newer functions such as glucose absorption. Some specific flavonoid species apparently affect an enzyme in the intestine that is required to break down complex carbohydrates such as starch, and also regular table sugar, into glucose units, said Frank Schonlau, Ph.D., director of scientific communications for Horphag Research (UK) Ltd., supplier of Pycnogenol®. Starch is composed of thousands of connected glucose entities and cannot be absorbed. He noted: Only as the enzyme alpha-glucosidase liberates glucose units from starch can it be absorbed and enter the bloodstream. Certain large-chain flavonoids slow-down the activity of alpha-glucosidase and thus slow-down the blood glucose increase after a meal. This is of particular importance for people struggling with overweight and elevated blood sugar levels, as metabolic syndrome. The flavonoids responsible for this usually comprise catechins from green tea, acerola and certain berriesand more recently, the French maritime pine bark extract (as Pycnogenol®). Pycnogenol was demonstrated to be fourtimes more effective than green tea extract due to its large-size procyanidin molecules.⁵⁶

And aside from traditional capsule and pill applications, flavonoids are found in a variety of functional foods and beveragesall at the consumers fingertips. We are seeing our antioxidant fruit and vegetable powders being put into clear drinks, functional ready-to-drink (RTD) and ready-to-mix (RTM) beverages, healthy snacks, snack and meal replacement bars, smoothies, candies and more, Hunter said.

As the many facets of flavonoids have, and continue to be, researched extensively, their applications grow with new discoveries. With cancer protective value and cited antioxidant benefits, these sugar-bound molecules are a sweet success story. Natures bountyfrom berries to sprouts, broccoli to grape seedis seen in the fields, off the vines, and into the growing market of flavonoids. 

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